Angiogenesis is a highly regulated process, whereby new blood vessels form from preexisting ones (Folkman J. Angiogenesis: an organizing principle for drug discovery Nat. Rev. Drug Discov. 2007; 6: 273-86). In adult mammals, physiologic angiogenesis is largely limited to the ovaries, uterus, and placenta, with the turnover rate of vascular endothelial cells being very low in most other tissues. Pathophysiologic angiogenesis is a characteristic of wound healing and diseased states, particularly cancer, where the number of proliferating endothelial cells increases significantly and the morphology of the vasculature is altered in multiple ways (Baluk P, Hashizume H, McDonald D M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 2005; 15: 102-11). For many types of cancer, as tumor cells undergo dysregulated proliferation, the tumor mass initially expands beyond the support capacity of the existing vasculature, leading to decreased levels of oxygen and nutrients and the accumulation of metabolic wastes. Tumor cells respond to this deterioration of the tumor microenvironment by up-regulating several proangiogenic factors, including vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factor, placental growth factor, and platelet-derived endothelial growth factor, which collectively activate quiescent endothelial cells and promote their migration into the tumor. This shift of the tumor microenvironment to an angiogenic state, or “angiogenic switch” (Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-64), is an important rate-limiting factor in tumor development. Despite the active angiogenesis induced by tumor cell-derived proangiogenic factors, structural defects associated with the tumor vasculature often lead to inefficient blood perfusion in established tumors, which contributes to tumor hypoxia. Tumor metastasis is also regulated by angiogenesis, as well as by lymphangiogenesis, where new lymphatic vessels are formed from preexisting ones (Christofori G. New signals from the invasive front. Nature 2006; 441: 444-50). Tumor cell dissemination, the first step in tumor metastasis, requires access to both blood and lymphatic circulation. Once successfully extravasated, the survival and further colonization of the disseminated tumor cells is dependent on angiogenesis at the secondary site. Angiogenesis is thus a key factor in the development and metastasis of a variety of tumor types and is an important hallmark of malignant disease. Moreover, angiogenesis presents unique opportunities for therapeutic intervention in cancer treatment, as first proposed by the late Judah Folkman more than thirty five years ago (Folkman J. Tumor angiogenesis: therapeutic implications. N Engl. J. Med. 1971; 285: 1182-6).
Today, inhibition of angiogenesis is recognized as new modality of cancer treatments. The targets of anti-angiogenic treatments are the proliferating/migrating endothelial cells into any tumor. Because this tumor-driven phenotype of endothelial cells differs from the quiescent endothelial cells lining blood vessels of healthy tissues, anti-angiogenic treatments were initially anticipated to be highly specific and thus safe drugs.
Recently, however, safety concerns were raised about anti-angiogenic drugs including anti-VEGF antibody (Avastin) and a variety of Tyrosine Kinase Inhibitors (Verheul and Pinedo., Nature Rev. Cancer, 7, 475-485 52007) (including bleeding, gastric perforation, hypertension and thrombotic events). The other biological roles played by angiogenic mediators or growth factors (such as VEGF) in maintaining the cardiovascular homeostasis are very likely to be the major cause of these life-threatening side effects.
Drugs with a higher selectivity for the tumor vasculature are therefore avidly needed.
Pathophysiologic hypoxia is actually recognized as a hallmark of most tumor types and documented to trigger angiogenesis. Even though angiogenesis aims at decreasing hypoxia, proliferating and migrating endothelial cells forming new vessels are per se exposed to low pO2. In addition, two other forms of hypoxia directly impact endothelial cells in tumors. First, cyclic hypoxia arising from variations in red blood cell flux is reported to occur within tumor microvessels, thereby exposing at least intermittently tumor endothelial cells to a hypoxic environment (Martinive et al. Mol. Cancer Ther. 2006 June; 5(6):1620-7; Baudelet C. et al. NMR Biomed. 2006 February; 19(1): 69-76; Dewhirst et al. Nature Rev. Cancer 8, 425-437 (June 2008); Dewhirst Cancer Res. 2007 Feb. 1; 67(3): 854-5). Second, longitudinal hypoxia describes the O2 gradient developing from the vessels supplying the tumor, i.e. the deeper the vessel penetrates in the tumor mass, the lesser oxygen is left available to diffuse in the surrounding tumor tissue.
As a summary, there is still a stringent need for potent tumor selective anti-angiogenic agents. Therefore a goal of the present invention is to satisfy this urgent need by identifying efficient pharmaceutically active compounds having tumor selective anti-angiogenic and/or cytotoxic activity.